scholarly journals Dual Inhibition of mTORC1/2 Reduces Migration of Cholangiocarcinoma Cells by Regulation of Matrixmetalloproteinases

2022 ◽  
Vol 9 ◽  
Author(s):  
Katharina Joechle ◽  
Huda Jumaa ◽  
Kerstin Thriene ◽  
Claus Hellerbrand ◽  
Birte Kulemann ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Dual Targeting ◽  
Anti Cancer ◽  
Metastatic Capacity ◽  
Tumor Entity ◽  
Dual Inhibition ◽  
Aggressive Tumor ◽  
And Migration ◽  
Systemic Therapies

Cholangiocarcinoma (CCA) is a rare but highly aggressive tumor entity for which systemic therapies only showed limited efficacy so far. As OSI-027—a dual kinase inhibitor targeting both mTOR complexes, mTORC1 and mTORC2 - showed improved anti-cancer effects, we sought to evaluate its impact on the migratory and metastatic capacity of CCA cells in vitro. We found that treatment with OSI-027 leads to reduced cell mobility and migration as well as a reduced surviving fraction in colony-forming ability. While neither cell viability nor proliferation rate was affected, OSI-027 decreased the expression of MMP2 and MMP9. Moreover, survival as well as anti-apoptotic signaling was impaired upon the use of OSI-027 as determined by AKT and MAPK blotting. Dual targeting of mTORC1/2 might therefore be a viable option for anti-neoplastic therapy in CCA.

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

17-β estradiol promotes autophagy and induces cellular senescence in breast cancer cells.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12523-e12523
Author(s):  
Khuloud Bajbouj ◽  
Jasmin Shafarin ◽  
Mawieh Hamad
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Mitochondrial Function ◽  
Breast Cancer Cells ◽  
Kinase Inhibitor ◽  
Ovarian Cancer Cells ◽  
Intracellular Iron ◽  
Mitochondrial Membrane Depolarization ◽  
Anti Cancer

e12523 Background: The fact that estrogen (17-β estradiol or E2) is a known carcinogen notwithstanding, mounting evidence suggest that E2 has the potential to exert anti-cancer effects against various forms of cancer. Using in vitro models we, and others, have previously demonstrated that E2 disrupts intracellular iron metabolism in such a way that arrests cell cycling in breast and ovarian cancer cells. However, the cellular and molecular correlates underlying this cytostatic effect of E2 in cancer cells remain elusive. Methods: In this study, metastatic (MDA-MB-231) and non-metastatic (MCF-7) breast cancer cells treated with 20 nM E2 were assessed for mitochondrial function, cell proliferation, apoptosis and senescence at different time points post treatment. Results: E2 treatment resulted in a significant mitochondrial membrane depolarization; an outcome that associated with a significant loss of mitochondrial function and the accumulation of auto-phagosomes. It also significantly upregulated the expression of the cell cycle regulating cyclin-dependent kinase inhibitor, p21 protein and enhanced the activation (de-phosphorylation) of the tumour suppressor retinoblastoma (Rb) protein. Although, as previously shown, E2 did not induced classis apoptosis; it resulted in a significant elevation in senescence-associated β- galactosidase levels. Conclusions: In summary, these findings suggest that E2 treatment mediates its anti-cancer potential by disrupting mitochondrial function and precipitating autophagy and cell senescence.

Abstract 332: Inhibition of the Enhancer of Zeste Homolog Family Mitigates Intimal Hyperplasia in Rat Carotid Arteries

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Mengxue Zhang ◽  
Bowen Wang ◽  
Go Urabe ◽  
Xudong Shi ◽  
Lian-Wang Guo
Keyword(s):  
Intimal Hyperplasia ◽  
Transcriptional Repression ◽  
Vascular Diseases ◽  
Inhibition Of Proliferation ◽  
Enhancer Of Zeste ◽  
Dual Inhibition ◽  
And Migration ◽  
Proliferation And Migration

Rationale: The enhancer of zeste homologs 1 and 2 (EZH1 and EZH2) are histone-lysine N-methyltransferases that modify histones by methylation which leads to transcriptional repression. It has recently been shown that EZH1 and EZH2 play an important role in various cancers. Whether they play a role in recurrent vascular diseases is not known. Objective: We assessed whether EZH1 and EZH2 are important contributors to the development of intimal hyperplasia (IH) and restenosis. Methods and Results: Following rat carotid balloon angioplasty, EZH2 showed highest expression at day 3 post procedure and then decreased at day 7 in injured arteries, as determined by Western blotting. Change of EZH1 is less prominent. Dual inhibition of EZH1 and EZH2 through peri-adventitial administration of a selective inhibitor, UNC-1999, effectively inhibited intimal hyperplasia, with ~40% reduction in the ratio of intima to media (I/M). Moreover, in cultured primary rat smooth muscle cells (SMCs) as well as MOVAS cells, pretreatment with 5μM UNC-1999 resulted in a 60% decrease in cell proliferation and ~80% reduction of migration that were stimulated by PDGF-BB. Simultaneous knockdown of EZH1 and EZH2, as well as knockdown of their shared scaffold protein(EED), led to effective inhibition of proliferation and migration of SMCs. However, knockdown of EZH2 alone did not recapitulate the effects of dual inhibition of EZH1 and EZH2. Conclusions: This study demonstrates that dual inhibition of EZH1 and EZH2, both histone modifiers, mitigates intimal hyperplasia in vivo and attenuates PDGF-BB stimulated SMC proliferation and migration in vitro.

scholarly journals Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aaminah Khan ◽  
Laura D. Gamble ◽  
Dannielle H. Upton ◽  
Caitlin Ung ◽  
Denise M. T. Yu ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Polyamine Synthesis ◽  
Dual Targeting ◽  
Significant Extension ◽  
Polyamine Transporter ◽  
Diffuse Intrinsic Pontine Gliomas ◽  
Rate Limiting ◽  
Systemic Therapies

AbstractDiffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumor, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that are essential for DNA replication, translation and cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine synthesis, is irreversibly inhibited by difluoromethylornithine (DFMO). Herein we show that polyamine synthesis is upregulated in DIPG, leading to sensitivity to DFMO. DIPG cells compensate for ODC1 inhibition by upregulation of the polyamine transporter SLC3A2. Treatment with the polyamine transporter inhibitor AMXT 1501 reduces uptake of polyamines in DIPG cells, and co-administration of AMXT 1501 and DFMO leads to potent in vitro activity, and significant extension of survival in three aggressive DIPG orthotopic animal models. Collectively, these results demonstrate the potential of dual targeting of polyamine synthesis and uptake as a therapeutic strategy for incurable DIPG.

scholarly journals Stress and its molecular consequences in cancer progression

2017 ◽  
Vol 71 (1) ◽  
pp. 0-0 ◽  
Author(s):  
Magdalena Surman ◽  
Marcelina E. Janik
Keyword(s):  
Cancer Patients ◽  
Cancer Progression ◽  
Hormone Receptors ◽  
Emotional Experience ◽  
Stress Hormones ◽  
Stress Factors ◽  
Physical Factors ◽  
Anti Cancer ◽  
And Migration

Stress, caused by psychological, physiological and physical factors has an adverse impact on human body homeostasis. There are two kind of stress: short-term and chronic. Cancer patients usually live under chronic stress, caused by diagnosis-related strong emotional experience and depression, resulting from various difficulties associated with disease progression and treatment. At the molecular level, stress factors induce production and secretion of stress-related hormones, such as catecholamines, glucocorticoids and dopamine (as a part of adaptational body response), which influence both normal and transformed cells through their specific receptors. The particular effects exerted by these molecules on cancer cells have been also observed in in vitro cultures and include changes in proliferation, apoptosis susceptibility and migration/invasion potential. As a result, it has been suggested that stress hormones may be responsible for progression of malignancy and thus accelerate the metastasis formation in cancer patients. However, the clinical data on correlation between stress and the patients survival, as well as the molecular analysis of stress hormone receptors expression and action in cancer cell, have not yet provided an unequivocal answer. For this reason, extensive studies, on molecular and clinical level are needed to fully determine stress impact on cancerprogression and on the effectiveness of anti-cancer treatment. Nowadays, it seems reasonable that the personalization of anti-cancer therapy should also focus on mental state of cancer patients, and provide them with psychological tools or techniques for stress management.

scholarly journals Tanshinone IIA Affects the Malignant Growth of Cholangiocarcinoma Cells by Inhibiting the PI3K-Akt-mTOR Pathway

2021 ◽  
Author(s):  
Huayuan Liu ◽  
Caiyun Liu ◽  
Mengya Wang ◽  
Dongxu Sun ◽  
Pengcheng Zhu ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Tanshinone Iia ◽  
Network Pharmacology ◽  
Protein Protein Interactions ◽  
Anticancer Effects ◽  
Anti Cancer ◽  
Cholangiocarcinoma Cell ◽  
And Migration ◽  
Proliferation And Migration

Abstract Purpose: In the present study, we aimed to find the target of Tanshinone IIA (Tan-IIA) in Cholangiocarcinoma by network pharmacology-based prediction and investigate the possible mechanism through experimental verification. Methods: In this study, we combined Tan-IIA-specific and Cholangiocarcinoma-specific targets with protein-protein interactions (PPI) to construct a Tan-IIA targets-Cholangiocarcinoma network, and network pharmacology approach was applied to identify potential targets and mechanisms of Tan-IIA in the treatment of Cholangiocarcinoma. The anti-cancer effects of Tan-IIA were investigated by using subcutaneous tumorigenic model in nude mice and in the human Cholangiocarcinoma cell lines in vitro. Results: Our results showed that Tan-IIA treatment considerably suppressed the proliferation and migration of Cholangiocarcinoma cells while inducing apoptosis of Cholangiocarcinoma cells. Western blot results demonstrated that the expression of PI3K, p-Akt, p-mTOR, and mTOR were inhibited by Tan-IIA. Meanwhile, After treatment with Tan-IIA, the level of Bcl2 was downregulated and cleaved caspase-3 expression increased. Further studies revealed that the anticancer effects of Tan-IIA were severely mitigated by pretreatment with a PI3K agonist.Conclusion: Our research provides a new anticancer strategy and strengthens support for the use of Tan-IIA as an anticancer drug for the treatment of CCA.

scholarly journals Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in Preclinical Models

2021 ◽  
Author(s):  
Shih-Shih Chen ◽  
Jacqueline Barrientos ◽  
Gerardo Ferrer ◽  
Priyadarshini Ravichandran ◽  
Michael Ibrahim ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Therapeutic Interventions ◽  
T Cell Migration ◽  
Dual Inhibition ◽  
And Migration ◽  
Phosphoinositide 3 Kinase

Abstract Inhibitors of Bruton’s Tyrosine Kinase (BTKi) and phosphoinositide 3-kinase (PI3Ki) have significantly improved therapy of chronic lymphocytic leukemia (CLL). However, the emergence of resistance to BTKi has introduced an unmet therapeutic need. Here we demonstrate in vitro and in vivo the essential roles of PI3K-δ for CLL B-cell survival and migration and of PI3K-γ in T-cell migration and macrophage polarization; and more efficacious inhibition in CLL-cell burden by dual inhibition of PI3K-δ,γ. We also report an ibrutinib-resistant CLL case, whose clone exhibited BTK and PLCγ2 mutations, responded immediately to single agent duvelisib with a redistribution lymphocytosis followed by a partial clinical remission associated with subsequent modulation of T and myeloid cells. CLL samples from patients progressed on ibrutinib were also responsive to duvelisib in patient-derived xenografts irrespective of BTK mutations. Our data support dual inhibition of PI3K-δ,γ as a valuable approach for therapeutic interventions, including patients refractory to BTKi.

scholarly journals Brassicasterol from Edible Aquacultural Hippocampus abdominalis Exerts an Anti-Cancer Effect by Dual-Targeting AKT and AR Signaling in Prostate Cancer

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 370
Author(s):  
Yinzhu Xu ◽  
Sooin Ryu ◽  
You-Kyung Lee ◽  
Hyo-Jeong Lee
Keyword(s):  
Prostate Cancer ◽  
Scientific Evidence ◽  
Specific Antigen ◽  
Bioactive Compound ◽  
Mass Spectrometry Data ◽  
Lncap Cells ◽  
Dual Targeting ◽  
Anti Cancer ◽  
Induced Apoptosis

In the Compendium of Materia Medica, seahorse (Hippocampus) is considered effective for the reinforcement of kidney and men’s health. However, the role of seahorse on human health lacks scientific evidence. Therefore, we evaluated the effect of seahorse on human prostate cancer using various in vitro methods and identified bioactive compound. Seahorse lipid extract (SHL) decreased androgen receptor (AR) and prostate-specific antigen (PSA) expression in dihydrotestosterone (DHT)-induced LNCaP cells of prostate cancer. Gas Chromatography (GC)-mass spectrometry data showed that brassicasterol was present in H. abdominalis. Brassicasterol downregulated the expression of AR and PSA in DHT-induced LNCaP cells. Brassicasterol induced apoptosis accompanied by sub-G1 phase arrest and inhibited migration in LNCaP cells. We confirmed that AKT and AR mediated the anti-cancer effect of brassicasterol using siRNA transfection. Brassicasterol exerts an anti-cancer effect in AR-independent cancer as well as in AR-dependent cells by AKT inhibiting. Our findings suggest that SHL has the anticancer potential via inhibition of AR and demonstrated that brassicasterol from H. abdominalis exerted an anti-cancer effect by dual-targeting AKT and AR signaling in prostate cancer.

scholarly journals Human Aurora kinase inhibitor Hesperadin reveals epistatic interaction between Plasmodium falciparum PfArk1 and PfNek1 kinases

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Belinda J. Morahan ◽  
Clarissa Abrie ◽  
Keith Al-Hasani ◽  
Mitchell B. Batty ◽  
Victoria Corey ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Resistance Mechanism ◽  
Genetic Selection ◽  
Aurora Kinase ◽  
Selective Inhibition ◽  
Mitotic Kinases ◽  
Anti Cancer ◽  
Selection For ◽  
Proliferation In Vitro

AbstractMitosis has been validated by numerous anti-cancer drugs as being a druggable process, and selective inhibition of parasite proliferation provides an obvious opportunity for therapeutic intervention against malaria. Mitosis is controlled through the interplay between several protein kinases and phosphatases. We show here that inhibitors of human mitotic kinases belonging to the Aurora family inhibit P. falciparum proliferation in vitro with various potencies, and that a genetic selection for mutant parasites resistant to one of the drugs, Hesperadin, identifies a resistance mechanism mediated by a member of a different kinase family, PfNek1 (PF3D7_1228300). Intriguingly, loss of PfNek1 catalytic activity provides protection against drug action. This points to an undescribed functional interaction between Ark and Nek kinases and shows that existing inhibitors can be used to validate additional essential and druggable kinase functions in the parasite.

scholarly journals Pharmacogenomics of Impaired Tyrosine Kinase Inhibitor Response: Lessons Learned From Chronic Myelogenous Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Meike Kaehler ◽  
Ingolf Cascorbi
Keyword(s):  
Tyrosine Kinase ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Survival Rates ◽  
Lessons Learned ◽  
Myelogenous Leukemia ◽  
Anti Cancer ◽  
Tki Resistance

The use of small molecules became one key cornerstone of targeted anti-cancer therapy. Among them, tyrosine kinase inhibitors (TKIs) are especially important, as they were the first molecules to proof the concept of targeted anti-cancer treatment. Since 2001, TKIs can be successfully used to treat chronic myelogenous leukemia (CML). CML is a hematologic neoplasm, predominantly caused by reciprocal translocation t(9;22)(q34;q11) leading to formation of the so-called BCR-ABL1 fusion gene. By binding to the BCR-ABL1 kinase and inhibition of downstream target phosphorylation, TKIs, such as imatinib or nilotinib, can be used as single agents to treat CML patients resulting in 80 % 10-year survival rates. However, treatment failure can be observed in 20-25 % of CML patients occurring either dependent or independent from the BCR-ABL1 kinase. Here, we review approved TKIs that are indicated for the treatment of CML, their side effects and limitations. We point out mechanisms of TKI resistance focusing either on BCR-ABL1-dependent mechanisms by summarizing the clinically observed BCR-ABL1-mutations and their implications on TKI binding, as well as on BCR-ABL1-independent mechanisms of resistances. For the latter, we discuss potential mechanisms, among them cytochrome P450 implications, drug efflux transporter variants and expression, microRNA deregulation, as well as the role of alternative signaling pathways. Further, we give insights on how TKI resistance could be analyzed and what could be learned from studying TKI resistance in CML in vitro.

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